Effect of P-glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine

Br J Clin Pharmacol. 2000 Sep;50(3):237-46. doi: 10.1046/j.1365-2125.2000.00226.x.


Aims: To investigate the effect of acute P-glycoprotein inhibition by the multidrug-resistance (MDR) modulator valspodar (SDZ PSC 833; PSC) on the pharmacokinetics, and potentially adverse pharmacodynamic effects of morphine, and its principal pharmacologically active metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).

Methods: In a double-blind, three-way crossover study, the pharmacokinetic and potentially adverse pharmacodynamic effects (reaction time, transcutaneous PCO2, blood pressure) of morphine were compared with and without acute inhibition of P-glycoprotein by PSC. The effects of PSC alone were also evaluated. The study was performed in 18 healthy male volunteers and pharmacodynamic effects analysed by measuring the area under the effect (AUE) curve. 150 mg PSC (or its placebo) was given as an i.v. infusion over 2 h. With the expected inhibition of Pgp 1 h after starting PSC infusion, 7.5 morphine HCl (or its placebo) was infused over 2 h.

Results: The infusion of PSC resulted in blood concentrations expected to inhibit Pgp mediated transport. While the pharmacokinetics of plasma morphine and M6G. were unaffected there was a small but statistically significant increase in the AUC and Cmax of M3G (11.8 and 8.3%, respectively). The t(1/2) and tmax were unaffected. The pharmacokinetic parameters of PSC were not affected by coadministration with morphine. PSC did not significantly affect the adverse events of morphine, as assessed by spontaneous reporting. Compared with PSC alone, morphine elicited an increase in reaction time (Emax 48 ms, compared with the predose absolute reaction time of 644 ms), which was not detected by the alertness-drowsiness score, indicating only slight sedation. There was a significant decrease in systolic blood pressure (Emin -9 mm Hg), and a trend for a fall in diastolic blood pressure (Emin -14.5 mm Hg) and respiratory rate (Emin -1.8 breath x min(-1)). For all these parameters, the effects of PSC/morphine were similar to that of PSC alone, suggesting some attenuation of morphine's effect. In contrast, morphine caused a significant increase in PCO2 (Emax 0.69 kPa) compared to PSC alone, indicating slight respiratory depression. This increase was similar to that of the PSC/morphine combination.

Conclusions: Acute inhibition of P-glycoprotein by PSC in this setting does not affect the pharmacokinetic or safety-related pharmacodynamic profile of morphine in a clinically significant manner.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors*
  • Adult
  • Analgesics, Opioid / adverse effects*
  • Analgesics, Opioid / pharmacokinetics*
  • Area Under Curve
  • Blood Gas Monitoring, Transcutaneous
  • Cross-Over Studies
  • Cyclosporins / pharmacokinetics
  • Cyclosporins / pharmacology*
  • Double-Blind Method
  • Drug Interactions
  • Half-Life
  • Humans
  • Injections, Intravenous
  • Male
  • Morphine / adverse effects*
  • Morphine / pharmacokinetics*
  • Morphine Derivatives / blood
  • Reaction Time / drug effects
  • Sleep Stages / drug effects


  • ATP Binding Cassette Transporter, Subfamily B
  • Analgesics, Opioid
  • Cyclosporins
  • Morphine Derivatives
  • morphine-6-glucuronide
  • Morphine
  • morphine-3-glucuronide
  • valspodar